Homocysteine and reactive oxygen species in metabolic syndrome, type 2 diabetes mellitus, and atheroscleropathy: The pleiotropic effects of folate supplementation

Nutrition Journal

Suresh C Tyagi¹  Melvin R Hayden² 

[1] Department of Physiology and Biophysics 500 South Preston Street University of Louisville Louisville, Kentucky 40292 USA;Department of Family and Community Medicine University of Missouri Columbia, Missouri PO BOX 1140 Lk. Rd. 5-87 Camdenton, Missouri 65020 USA

关键词: Oxidative stress;    Nitric Oxide Synthase;    Nitric Oxide;    Folic acid;    Folate Shuttle;    eNO;    eNOS;    BH4;    Atherosclerosis;   

Others  :  1151934
DOI  :  10.1186/1475-2891-3-4

 received in 2004-02-05, accepted in 2004-05-10,  发布年份 2004

【 摘 要 】

Homocysteine has emerged as a novel independent marker of risk for the development of cardiovascular disease over the past three decades. Additionally, there is a graded mortality risk associated with an elevated fasting plasma total homocysteine (tHcy). Metabolic syndrome (MS) and type 2 diabetes mellitus (T2DM) are now considered to be a strong coronary heart disease (CHD) risk enhancer and a CHD risk equivalent respectively. Hyperhomocysteinemia (HHcy) in patients with MS and T2DM would be expected to share a similar prevalence to the general population of five to seven percent and of even greater importance is: Declining glomerular filtration and overt diabetic nephropathy is a major determinant of tHcy elevation in MS and T2DM.

There are multiple metabolic toxicities resulting in an excess of reactive oxygen species associated with MS, T2DM, and the accelerated atherosclerosis (atheroscleropathy). HHcy is associated with an increased risk of cardiovascular disease, and its individual role and how it interacts with the other multiple toxicities are presented.

The water-soluble B vitamins (especially folate and cobalamin-vitamin B₁₂) have been shown to lower HHcy. The absence of the cystathionine beta synthase enzyme in human vascular cells contributes to the importance of a dual role of folic acid in lowering tHcy through remethylation, as well as, its action of being an electron and hydrogen donor to the essential cofactor tetrahydrobiopterin. This folate shuttle facilitates the important recoupling of the uncoupled endothelial nitric oxide synthase enzyme reaction and may restore the synthesis of the omnipotent endothelial nitric oxide to the vasculature.

【 授权许可】

   
2004 Hayden and Tyagi; licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

Figure 7.

【 参考文献 】

• [1]DuVigneaud VE: A Trail of Research in Sulfur Chemistry. Ithaca, NY: Cornell University Press; 1952.
• [2]McCully KS: Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis. Am J Pathol 1969, 56(1):111-128.
• [3]Stampfer MJ, Malinow MR, Willett WC, Newcomer L, Upson B, Ullmann D, Tishler P, Hennekens CH: A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in US physicians. JAMA 1992, 268:877-881.
• [4]Arnesen E, Refsum H, Bonaa KH, Ueland PM, Forde OH, Nordrehaug JE: Serum total homocysteine and coronary heart disease. Int J Epidemiol 1995, 24(4):704-709.
• [5]Boushey CJ, Beresford SA, Omenn GS, Motulsky AG: A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes. JAMA 1995, 274(13):1049-1057.
• [6]Graham IM, Daly LE, Refsum HM, Robinson K, Brattstrom LE, Ueland PM: Plasma homocysteine as a risk factor for vascular disease. The European Concerted Action Project. JAMA 1997, 277(22):1775-1781.
• [7]Wald NJ, Watt HC, Law MR, Weir DG, McPartlin J, Scott JM: Homocysteine and ischemic heart disease: results of a prospective study with implications regarding prevention. Arch Intern Med 1998, 158(8):862-867.
• [8]Hoogeveen EK, Kostense PJ, Beks PJ, Mackaay AJ, Jakobs C, Bouter LM, Heine RJ, Stehouwer CD: Hyperhomocysteinemia is associated with an increased risk of cardiovascular disease, especially in non-insulin-dependent diabetes mellitus: a population-based study. Arterioscler Thromb Vasc Biol 1998, 18(1):133-138.
• [9]Welch GN, Loscalzo J: Homocysteine and atherothrombosis. N Engl J Med 1998, 338(15):1042-50.
• [10]Stehouwer CD, Weijenberg MP, van den Berg M, Jakobs C, Feskens EJ, Kromhout D: Serum homocysteine and risk of coronary heart disease and cerebrovascular disease in elderly men: a 10-year follow-up. Arterioscler Thromb Vasc Biol 1998, 18(12):1895-1901.
• [11]Kark JD, Selhub J, Adler B, Gofin J, Abramson JH, Friedman G, Rosenberg IH: Nonfasting plasma total homocysteine level and mortality in middle-aged and elderly men and women in Jerusalem. Ann Intern Med 1999, 131(5):321-330.
• [12]Hoogeveen EK, Kostense PJ, Jakobs C, Dekker JM, Nijpels G, Heine RJ, Bouter LM, Stehouwer CD: Hyperhomocysteinemia increases risk of death, especially in type 2 diabetes : 5-year follow-up of the Hoorn Study. Circulation 2000, 101(13):1506-1511.
• [13]Boers GH: Mild hyperhomocysteinemia is an independent risk factor of arterial vascular disease. Semin Thromb Hemost 2000, 26(3):291-295.
• [14]Blom HJ: Consequences of homocysteine export and oxidation in the vascular system. Semin Thromb Hemost 2000, 26(3):227-232.
• [15]Jakubowski H, Zhang L, Bardeguez A, Aviv A: Homocysteine thiolactone and protein homocysteinylation in human endothelial cells: implications for atherosclerosis. Circ Res 2000, 87(1):45-51.
• [16]Misra HP: Generation of superoxide free radical during the autoxidation of thiols. J Biol Chem 1974, 249(7):2151-2155.
• [17]Jakubowski H: Homocysteine is a protein amino acid in humans. Implications for homocysteine-linked disease. J Biol Chem 2002, 277(34):30425-3048.
• [18]Schnyder G, Roffi M, Pin R, Flammer Y, Lange H, Eberli FR, Meier B, Turi ZG, Hess OM: Decreased rate of coronary restenosis after lowering of plasma homocysteine levels. N Engl J Med 2001, 345(22):1593-1600.
• [19]Schnyder G, Roffi M, Flammer Y, Pin R, Hess OM: Effect of homocysteine-lowering therapy with folic acid, vitamin B12, and vitamin B6 on clinical outcome after percutaneous coronary intervention: the Swiss Heart study: a randomized controlled trial. JAMA 2002, 288(8):973-979.
• [20]Schnyder G, Rouvinez G: Total plasma homocysteine and restenosis after percutaneous coronary angioplasty: current evidence. Ann Med 2003, 35(3):156-163.
• [21]Hodish I, Matetzky S, Sela BA, Guetta V, Goldenberg I, Doolman R, Freimark D, Hod H, Selah BA: Effect of elevated homocysteine levels on clinical restenosis following percutaneous coronary intervention. Cardiology 2002, 97(4):214-217.
• [22]Mahanonda N, Leowattana W, Kangkagate C, Lolekha P, Pokum S: Homocysteine and restenosis after percutaneous coronary intervention. J Med Assoc Thai 2001, 84(Suppl 3):S636-644.
• [23]Genser D, Prachar H, Hauer R, Halbmayer WM, Mlczoch J, Elmadfa I: Relation of homocysteine, vitamin B(12), and folate to coronary in-stent restenosis. Am J Cardiol 2002, 89(5):495-499.
• [24]Liem A, Reynierse-Buitenwerf GH, Zwinderman AH, Jukema JW, van Veldhuisen DJ: Secondary prevention with folic acid: effects on clinical outcomes. J Am Coll Cardiol 2003, 41(12):2105-2113.
• [25]Guilland JC, Favier A, Potier de Courcy G, Galan P, Hercberg S: Hyperhomocysteinemia: an independent risk factor or a simple marker of vascular disease? 1. Basic data. Pathol Biol (Paris) 2003, 51(2):101-110.
• [26]Guilland JC, Favier A, Potier de Courcy G, Galan P, Hercberg S: Hyperhomocysteinemia: an independent risk factor or a simple marker of vascular disease? 2. Epidemiological data. Pathol Biol (Paris) 2003, 51(2):111-121.
• [27]Finkelstein JD: The metabolism of homocysteine: pathways and regulation. Eur J Pediatr 1998, 157(Suppl 2):S40-44.
• [28]Finkelstein JD: Methionine metabolism in mammals. J Nutr Biochem 1990, 1:228-237.
• [29]Hoogeveen EK, Kostense PJ, Jakobs C, Dekker JM, Nijpels G, Heine RJ, Bouter LM, Stehouwer CD: Hyperhomocysteinemia increases risk of death, especially in type 2 diabetes: 5-year follow-up of the Hoorn Study. Circulation 2000, 101(13):1506-1511.
• [30]Hoogeveen EK, Kostense PJ, Beks PJ, Mackaay AJ, Jakobs C, Bouter LM, Heine RJ, Stehouwer CD: Hyperhomocysteinemia is associated with an increased risk of cardiovascular disease, especially in non-insulin-dependent diabetes mellitus: a population-based study. Arterioscler Thromb Vasc Biol 1998, 18(1):133-138.
• [31]Hayden MR, Tyagi SC: Islet redox stress: the manifold toxicities of insulin resistance, metabolic syndrome and amylin derived islet amyloid in type 2 diabetes mellitus. JOP 2002, 3(4):86-108.
• [32]Hayden MR, Tyagi SC: Intimal redox stress: Accelerated atherosclerosis in metabolic syndrome and type 2 diabetes mellitus. Atheroscleropathy. Cardiovasc Diabetol 2002, 1(1):3. BioMed Central Full Text
• [33]Jacques PF, Bostom AG, Williams RR, Ellison RC, Eckfeldt JH, Rosenberg IHk, Selhub J, Rozen R: Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations. Circulation 1996, 93:7-9.
• [34]Arruda VR, von Zuben PM, Chiaparini LC, Annichino-Bizzacchi JM, Costa FF: The mutation Ala677 → Val in the methylene tetrahydrofolate reductase gene: a risk factor for arterial disease and venous thrombosis. Thromb Haemost 1997, 77:818-821.
• [35]Feix A, Fritsche-Polanz R, Kletzmayr J, Vychytil A, Horl WH, Sunder-Plassmann G, Fodinger M: Increased prevalence of combined MTR and MTHFR genotypes among individuals with severely elevated total homocysteine plasma levels. Am J Kidney Dis 2001, 38:956-964.
• [36]Woo KS, Chook P, Lolin YI, Sanderson JE, Metreweli C, Celermajer DS: Folic acid improves arterial endothelial function in adults with hyperhomocystinemia. J Am Coll Cardiol 1999, 34:2002-2006.
• [37]Audelin MC, Genest J Jr: Homocysteine and cardiovascular disease in diabetes mellitus. Atherosclerosis 2001, 159:497-511.
• [38]Rosolova H, Simon J, Mayer O Jr, Racek J, Dierze T, Jacobsen DW: Unexpected inverse relationship between insulin resistance and serum homocysteine in healthy subjects. Physiol Res 2002, 51(1):93-98.
• [39]Hiragushi K, Sugimoto H, Shikata K, Yamashita T, Miyatake N, Shikata Y, Wada J, Kumagai I, Fukushima M, Makino H: Nitric oxide system is involved in glomerular hyperfiltration in Japanese normo- and micro-albuminuric patients with type 2 diabetes. Diabetes Res Clin Pract 2001, 53(3):149-159.
• [40]Henegar JR, Bigler SA, Henegar LK, Tyagi SC, Hall JE: Functional and structural changes in the kidney in the early stages of obesity. J Am Soc Nephrol 2001, 12(6):1211-1217.
• [41]Apakkan Aksun S, Ozmen B, Ozmen D, Parildar Z, Senol B, Habif S, Mutaf I, Turgan N, Bayindir O: Serum and urinary nitric oxide in Type 2 diabetes with or without microalbuminuria. Relation to glomerular hyperfiltration. J Diabetes Complications 2003, 17(6):343-348.
• [42]Fodinger M, Mannhalter C, Wolfl G, Pabinger I, Muller E, Schmid R, Horl WH, Sunder-Plassmann G: Mutation (677 C to T) in the methylenetetrahydrofolate reductase gene aggravates hyperhomocysteinemia in hemodialysis patients. Kidney Int 1997, 52:517-523.
• [43]Weiss N, Heydrick S, Zhang YY, Bierl C, Cap A, Loscalzo J: Cellular redox state and endothelial dysfunction in mildly hyperhomocysteinemic cystathionine beta-synthase-deficient mice. Arterioscler Thromb Vasc Biol 2002, 22:34-41.
• [44]Simon DI, Mullins ME, Jia L, Gaston B, Singel DJ, Stamler JS: Polynitrosylated proteins: characterization, bioactivity and functional consequences. Proc Natl Acad Sci USA 1996, 93:4736-4741.
• [45]Beckman JS, Koppenol WH: Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly. Am J Physiol 1996, 271:C1424-1437.
• [46]Beckman JS, Beckman TW, Chen J, Marshall PA, Freeman BA: Apparent hydroxy radical production by peroxynitrite: Implications for endothelial injury from nitric oxide and superoxide. Proc Natl Acad Sci USA 1990, 87:1620-1624.
• [47]Mujumdar VS, Aru GM, Tyagi SC: Induction of oxidative stress by homocyst(e)ine impairs endothelial function. J Cell Biochem 2001, 82:491-500.
• [48]Maejima K, Nakano S, Himeno M, Tsuda S, Makiishi H, Ito T, et al.: Increased basal levels of plasma nitric oxide in Type 2 diabetic subjects. Relationship to microvascular complications. J Diabetes Complications 2001, 15:135-143.
• [49]Zhang X, Li H, Jin H, Ebin Z, Brodsky S, Goligorsky MS: Effects of homocysteine on endothelial nitric oxide production. Am J Physiol Renal Physiol 2000, 279:F671-678.
• [50]Li H, Lewis A, Brodsky S, Rieger R, Iden C, Goligorsky MS: Homocysteine induces 3-hydroxy-3-methylglutaryl coenzyme A reductase in vascular endothelial cells. A mechanism for development of atherosclerosis? Circulation 2002, 105:1037-1043.
• [51]Stuhlinger MC, Tsao PS, Her JH, Kimoto M, Balint RF, Cooke JP: Homocysteine impairs the nitric oxide synthase pathway: role of asymmetric dimethylarginine. Circulation 2001, 104(21):2569-2575.
• [52]Hayden MR, Tyagi SC: Is type 2 diabetes mellitus a vascular disease (atheroscleropathy) with hyperglycemia a late manifestation? The role of NOS, NO, and redox stress. Cardiovasc Diabetol 2003, 2:2. BioMed Central Full Text
• [53]Noiri E, Satoh H, Taguchi J, Brodsky SV, Nakao A, Ogawa Y, Nishijima S, Yokomizo T, Tokunaga K, Fujita T: Association of eNOS Glu298Asp polymorphism with end-stage renal disease. Hypertension 2002, 40(4):535-540.
• [54]Brown KS, Kluijtmans LA, Young IS, Woodside J, Yarnell JW, McMaster D, Murray L, Evans AE, Boreham CA, McNulty H, Strain JJ, Mitchell LE, Whitehead AS: Genetic Evidence That Nitric Oxide Modulates Homocysteine: The NOS3 894TT Genotype Is a Risk Factor for Hyperhomocystenemia. Arterioscler Thromb Vasc Biol 2003, 23(6):1014-1020.
• [55]Stern MP: Diabetes and cardiovascular disease. The "common soil" hypothesis. Diabetes 1995, 44(4):369-374.
• [56]Gazzaruso C, Garzaniti A, Giordanetti S, Falcone C, Fratino P: Silent coronary artery disease in type 2 diabetes mellitus: the role ofLipoprotein(a), homocysteine and apo(a) polymorphism. Cardiovasc Diabetol 2002, 1(1):5. BioMed Central Full Text
• [57]Meigs JB, Jacques PF, Selhub J, Singer DE, Nathan DM, Rifai N, D'Agostino RB Sr, Wilson PW, Framingham Offspring Study: Fasting plasmahomocysteine levels in the insulin resistance syndrome: the Framingham offspring study. Diabetes Care 2001, 24(8):1403-1410.
• [58]Passaro A, D'Elia K, Pareschi PL, Calzoni F, Carantoni M, Fellin R, Solini A: Factors influencing plasma homocysteine levels in type 2 diabetes. Diabetes Care 2000, 23(3):420-421.
• [59]Passaro A, Calzoni F, Volpato S, Nora ED, Pareschi PL, Zamboni PF, Fellin R, Solini A: Effect of metabolic control on homocysteine levels in type 2 diabetic patients: a 3-year follow-up. J Intern Med 2003, 254(3):264-271.
• [60]Burke AP, Fonseca V, Kolodgie F, Zieske A, Fink L, Virmani R: Increased serum homocysteine and sudden death resulting from coronary atherosclerosis with fibrous plaques. Arterioscler Thromb Vasc Biol 2002, 22(11):1936-1941.
• [61]Tenenbaum A, Fisman EZ, Motro M: Metabolic syndrome and type 2 diabetes mellitus: focus on peroxisome proliferator activated receptors (PPAR). Cardiovasc Diabetol 2003, 2(1):4. BioMed Central Full Text
• [62]Dandona P: Insulin resistance and endothelial dysfunction in atherosclerosis: implications and interventions. Diabetes Technol Ther 2002, 4(6):809-815.
• [63]Hsueh WA, Jackson S, Law RE: Control of vascular cell proliferation and migration by PPAR-gamma: a new approach to the macrovascularcomplications of diabetes. Diabetes Care 2001, 24(2):392-397.
• [64]Hsueh WA: PPAR-gamma effects on the vasculature. J Investig Med 2001, 49(1):127-129.
• [65]Satoh N, Ogawa Y, Usui T, Tagami T, Kono S, Uesugi H, Sugiyama H, Sugawara A, Yamada K, Shimatsu A, Kuzuya H, Nakao K: Antiatherogenic effect of pioglitazone in type 2 diabetic patients irrespective of the responsiveness to its antidiabetic effect. Diabetes Care 2003, 26(9):2493-2499.
• [66]Desvergne B, Wahli W: Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocr Rev 1999, 20(5):649-688.
• [67]Kersten S, Desvergne B, Wahli W: Roles of PPARs in health and disease. Nature 2000, 405(6785):421-424.
• [68]Hsueh WA, Law R: The central role of fat and effect of peroxisome proliferator-activated receptor-gamma on progression of insulin resistance and cardiovascular disease. Am J Cardiol 2003, 92(4A):3J-9J.
• [69]Fonseca V, Keebler M, Dicker-Brown A, Desouza C, Poirier LA, Murthy SN, McNamara DB: The effect of troglitazone on plasma homocysteine, hepatic and red blood cell S-adenosyl methionine, and S-adenosyl homocysteine and enzymes in homocysteine metabolism in Zucker rats. Metabolism 2002, 51(6):783-786.
• [70]Tao L, Liu HR, Gao E, Teng ZP, Lopez BL, Christopher TA, Ma XL, Batinic-Haberle I, Willette RN, Ohlstein EH, Yue TL: Antioxidative, Antinitrative, and Vasculoprotective Effects of a Peroxisome Proliferator-Activated Receptor-{gamma} Agonist in Hypercholesterolemia. Circulation 2003, 108(22):2805-2811.
• [71]Tyagi SC, Hayden MR: Role of nitric oxide in matrix remodeling in diabetes and heart failure. Heart Fail Rev 2003, 8(1):23-28.
• [72]Sood HS, Hunt MJ, Tyagi SC: Peroxisome proliferator ameliorates endothelial dysfunction in a murine model of hyperhomocysteinemia. Am J Physiol Lung Cell Mol Physiol 2003, 284(2):L333-341.
• [73]Hunt MJ, Tyagi SC: Peroxisome proliferators compete and ameliorate Hcy-mediated endocardial endothelial cell activation. Am J Physiol Cell Physiol 2002, 283(4):C1073-1079.
• [74]Mujumdar VS, Tummalapalli CM, Aru GM, Tyagi SC: Mechanism of constrictive vascular remodeling by homocysteine: role of PPAR. Am J Physiol Cell Physiol 2002, 282(5):C1009-1015.
• [75]Flynn MA, Herbert V, Nolph GB, Krause G: Atherogenesis and the homocysteine-folate-cobalamin triad: do we need standardized analyses? J Am Coll Nutr 1997, 16(3):258-267.
• [76]Tyagi SC: Homocyst(e)ine and heart disease: Pathophysiology of extracellular matrix. Clin Exp Hypertens 1999, 21(3):181-198.
• [77]Miller A, Mujumdar V, Palmer L, Bower JD, Tyagi SC: Reversal of endocardial endothelial dysfunction by folic acid in homocysteinemic hypertensive rats. Am J Hypertens 2002, 15(2 Pt 1):157-163.
• [78]Mujumdar VS, Tummalapalli CM, Aru GM, Tyagi SC: Mechanism of constrictive vascular remodeling by homocysteine: role of PPAR. Am J Physiol Cell Physiol 2002, 282(5):C1009-1015.
• [79]Mujumdar VS, Hayden MR, Tyagi SC: Homocyst(e)ine induces calcium second messenger in vascular smooth muscle cells. J Cell Physiol 2000, 183(1):28-36.
• [80]Miller A, Mujumdar V, Shek E, Guillot J, Angelo M, Palmer L, Tyagi SC: Hyperhomocyst(e)inemia induces multi organ damage. Heart Vessels 2000, 15(3):135-143.
• [81]Stanger O: Physiology of folic acid in health and disease. Current Drug Metabolism 2002, 3(2):211-223.
• [82]Van Etten RW, De Koning EJ, Verhaar MC, Gaillard CA, Rabelink TJ: Impaired NO-dependent vasodilation in patients with Type II (non-insulin-dependent) diabetes mellitus is restored by acute administration of folate. Diabetologia 2002, 45(7):1004-1010.
• [83]Doshi SN, McDowell IF, Moat SJ, Payne N, Durrant HJ, Lewis MJ, Goodfellow J: Folic acid improves endothelial function in coronary artery disease via mechanisms largely independent of homocysteine lowering. Circulation 2002, 105(1):22-26.
• [84]Hayden MR, Tyagi SC: Myocardial redox stress and remodeling in metabolic syndrome, type 2 diabetes mellitus and congestive heart failure. Med Sci Monit 2003, 9(7):SR35-52.
• [85]Lindenbaum J, Savage DG, Stabler SP, Allen RH: Diagnosis of cobalamin deficiency: II. Relative sensitivities of serum cobalamin, methylmalonic acid, and total homocysteine concentrations. Am J Hematol 1990, 34:99-107.
• [86]Savage DG, Lindenbaum J, Stabler SP, Allen RH: Sensitivity of serum methylmalonic acid and total homocysteine determinations for diagnosis of cobalamin and folate deficiencies. Am J Med 1994, 96:239-246.
• [87]Carmel R, Green R, Rosenblatt DS, Watkins D: Update on Cobalamin, Folate, and Homocysteine. Hematology (Am Soc Hematol Educ Program) 2003, 62-81.
• [88]Flynn MA, Singh A, Slaughter J, King P, Krause G, Herbert V, Thomas W: Interrelationship of homocysteine-cobalamin-folate indices in human subjects of various ages: can hyper-homocyteinemia be relieved with B-12 supplementation? Mo Med 2003, 100(2):155-158.
• [89]Liaugaudas G, Jacques PF, Selhub J, Rosenberg IH, Bostom AG: Renal insufficiency, vitamin B(12) status, and population attributable risk for mild hyperhomocysteinemia among coronary artery disease patients in the era of folic acid-fortified cereal grain flour. Arterioscler Thromb Vasc Biol 2001, 21:849-851.
• [90]Andres E, Noel E, Goichot B: Metformin-associated vitamin B12 deficiency. Arch Intern Med 2002, 162(19):2251-2252.
• [91]Filioussi K, Bonovas S, Katsaros T: Should we screen diabetic patients using biguanides for megaloblastic anaemia? Aust Fam Physician 2003, 32(5):383-384.
• [92]Homocysteine Lowering Trialists' Collaboration: Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomized trials. BMJ 1998, 316:894-898.
• [93]Johnson MA, Hawthorne NA, Brackett WR, Fischer JG, Gunter EW, Allen RH, Stabler SP: Hyperhomocysteinemia and vitamin B-12 deficiency in elderly using Title IIIc nutrition services. Am J Clin Nutr 2003, 77(1):211-220.
• [94]Ridker PM, Rifai N, Pfeffer MA, Sacks FM, Moye LA, Goldman S, Flaker GC, Braunwald E: Inflammation, pravastatin, and the risk of coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events (CARE) Investigators. Circulation 1998, 98(9):839-844.
• [95]Ridker PM, Morrow DA: C-reactive protein, inflammation, and coronary risk. Cardiol Clin 2003, 21(3):315-325.
• [96]Ridker PM: High-sensitivity C-reactive protein and cardiovascular risk: rationale for screening and primary prevention. Am J Cardiol 2003, 92(4B):17K-22K.
• [97]Ridker PM: Clinical application of C-reactive protein for cardiovascular disease detection and prevention. Circulation 2003, 107(3):363-369.
• [98]Ridker PM, Shih J, Cook TJ, Clearfield M, Downs JR, Pradhan AD, Weis SE, Gotto AM Jr, Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) Investigators: Plasma homocysteine concentration, statin therapy, and the risk of first acute coronary events. Circulation 2002, 105(15):1776-1779.
• [99]Verhaar MC, Stroes E, Rabelink TJ: Folates and cardiovascular disease. Arterioscler Thromb Vasc Biol 2002, 22(1):6-13.
• [100]Ajabnoor MA, AL-Ama MN, Banjar Z, Rafee AA, Sheweita SA: Homocysteine level and other biochemical parameters in cardiovascular disease patients with diabetes mellitus. Med Sci Monit 2003, 9(12):CR523-CR527.
• [101]Nygard O, Nordrehaug JE, Refsum H, Ueland PM, Farstad M, Vollset SE: Plasma homocysteine levels and mortality in patients with coronary artery disease. N Engl J Med 1997, 337(4):230-236.
• [102]Dandona P: Editoral. Metabolic Syndrome and Related Disorders 2003, 1(2):93.
• [103]Fonseca VA: Hyperhomocysteinemia and the Metabolic Syndrome: Is There a Connection? Metabolic Syndrome and Related Disorders 2003, 1(2):95-96.
• [104]Joseph J, Joseph L: Hyperhomocysteinemia and cardiovascular disease: New mechanisms beyond atherosclerosis. Metabolic Syndrome and Related Disorders 2003, 1(2):97-104.
• [105]Becker A, Smulders YM, Guldener CV, Stehouwer CDA: Epidemiology of homocysteine as a risk factor in diabetes. Metabolic Syndrome and Related Disorders 2003, 1(2):105-120.
• [106]Randeva HS: Hormonal regulation of homocysteine. Metabolic Syndrome and Related Disorders 2003, 1(2):121-128.
• [107]Murthy SN, Matta AS, Mondal D, McNamara DB: Methods in assessing homocysteine metabolism. Metabolic Syndrome and Related Disorders 2003, 1(2):129-140.
• [108]Kulkarni K, Richard BC: Lifestyle, homocysteine, and the metabolic syndrome. Metabolic Syndrome and Related Disorders 2003, 1(2):141-147.
• [109]Asnani S, Chan E, Murthy SN, McNamare DB, Fonseca VA: Effect of Pharmacological treatments for diabetes on homocysteine. Metabolic Syndrome and Related Disorders 2003, 1(2):149-158.
• [110]Chan E, Fonseca VA: Management of hyperhomocysteinemia. Metabolic Syndrome and Related Disorders 2003, 1(2):159-170.
• [111]Soinio M, Marniemi J, Laakso M, Lehto S, Ronnemaa T: Elevated plasma homocysteine level is an independent predictor of coronary heart disease events in patients with type 2 diabetes mellitus. Ann Intern Med 2004, 140(2):94-100.